Liver-Enriched Transcription Factor CREBH Interacts With Peroxisome Proliferator-Activated Receptor α to Regulate Metabolic Hormone FGF21

Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes. In this study, we demonstrated that the liver-enriched transcription factor CREBH (cAMP-responsive element binding protein, hepatocyte specific) and peroxisome proliferator-activated receptor alpha (PPAR alpha) function as binary transcriptional activators to regulate lipid metabolism by activating fibroblast growth factor 21 (FGF21), a hepatic hormone that regulates whole-body energy homeostasis. Gain-and loss-of-function studies indicated that CREBH regulates triglyceride and fatty acid metabolism in animals under fasting or on an atherogenic high-fat (AHF) diet. CREBH and PPAR alpha act as interactive trans-activators that regulate each other for their expression. Activated CREBH protein interacts with PPAR alpha to form a functional complex upon fasting or the AHF diet, and both factors are required for induction of the metabolic hormone FGF21. The CREBH-PPAR alpha complex was found to bind to integrated CRE-PPAR-responsive element-binding motifs in the FGF21 gene promoter. Whereas CREBH and PPAR alpha function in synergy to activate FGF21 gene expression, PPAR alpha relies on CREBH to exert its trans-activation effect on FGF21. Supporting the key role of CREBH in regulating FGF21, infusion of recombinant FGF21 protein can reverse hypertriglyceridemia and hypoketonemia and partially rescue nonalcoholic steatohepatitis developed in the CREBH-null mice after the AHF diet. Our study demonstrated a transcriptional regulatory axis of CREBH-PPAR alpha-FGF21 in maintaining lipid homeostasis under metabolic stress. The functional relationship between CREBH and PPAR alpha in regulating FGF21 may represent an important transcriptional coactivation mechanism that orchestrates the processes of energy supply upon metabolic alteration.